Compositions and methods for neuroprotectin

ABSTRACT

Disclosed herein are neuroprotective compounds. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of neurodegenerative conditions are provided.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/837,365, entitled “Role of Liminoid Compounds asNeuroprotective Agents,” filed Aug. 11, 2006, the contents of which areincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Neurodegenerative conditions such as Alzheimer's Disease, multiplesclerosis, AIDS-related dementia, Huntington's Disease, stroke, andspinal cord trauma are characterized by extensive loss of neurons orglia.

SUMMARY OF THE INVENTION

Described herein are neuroprotective compounds. Also described hereinare pharmaceutical formulations comprising such neuroprotectivecompounds, and methods for using such neuroprotective compounds in theprophylaxis and treatment of neurodegenerative conditions.

Accordingly, in one aspect provided herein is a pharmaceuticalcomposition comprising at least one compound having the structure ofFormula I:

wherein each compound of Formula I is in a substantially purified form;andY₁ is O and Y₂ is OH, O-alkyl, O-(hydroxyalkyl) or O-(alkoxyalkyl); orY₁ and Y₂ together form a furan group;R₁ and R₂ together form a substituted cycloalkyl or cycloalkenyl group;and

is selected from

,

wherein X₄ and R₂ together form a substituted heteroalicyclic groupprovided that R₁ is H; orpharmaceutically acceptable salts, esters, prodrugs, or metabolitesthereof;or ester derivatives, saccharide derivatives, or —(CH₂CH₂O)_(n)CH₃derivatives thereof, where n is 1 to 100;and a pharmaceutically acceptable excipient.

In a further embodiment, the at least one compound of Formula I has astructure selected from:

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₄ and R₅ together form a substituted cycloalkyl or cycloalkenylgroup.

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₆ and R₇ together form a substituted cycloalkyl or cycloalkenylgroup; and X₁ is selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl),O-(alkoxyalkyl), or O—C(O)-alkyl.

In a further embodiment, the at least one compound of Formula I has astructure selected from:

wherein R₈ and R₉ are independently H or alkyl;X₂ and X₃ are independently selected from H, oxo, OH, O-alkyl,O-(hydroxyalkyl), O-(alkoxyalkyl), or O—C(O)-alkyl; and

is selected from

or

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₄ and R₅ together form a substituted cycloalkyl or cycloalkenylgroup.

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₆ and R₇ together form a substituted cycloalkyl or cycloalkenylgroup; andX₁ selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl), O-(alkoxyalkyl),or O—C(O)-alkyl.

In a further embodiment, the at least one compound of Formula I has astructure selected from:

wherein R₈ and R₉ are independently H or alkyl;X₂ and X₃ are independently selected from H, oxo, OH, O-alkyl,O-(hydroxyalkyl), O-(alkoxyalkyl), or O—C(O)-alkyl; and

is selected from

or

In a further embodiment, the at least one compound of Formula I has thestructure:

X₄ and R₁₀ together form a substituted heteroalicyclic group.

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₁₁ and R₁₂ together form a substituted cycloalkyl orcycloalkenyl group.

In a further embodiment, the at least one compound of Formula I has thestructure:

wherein R₁₃ and R₁₄ are independently H or alkyl;X₅ is selected from H, oxo, OH, O-alkyl, O-(hydroxyalkyl),O-(alkoxyalkyl), or O—C(O)-alkyl; andR₁₅ is alkyl-C(O)O-alkyl.

In another aspect provided herein is a pharmaceutical compositioncomprising at least one compound having the structure of Formula II:

wherein Het_(o) is a substituted or unsubstituted oxygen-containingaromatic or non-aromatic heterocycle; L is a bond or an alkylene group;each

is independently selected from

,

or

provided that no two adjacent

groups are adjacent

or

groups;each X₂₀, X₂₁, X₂₂, X₂₃, and X₂₄ is independently selected from H, oxo,OH, OC(O)-alkyl, O-(hydroxyalkyl), O-(alkoxyalkyl), or O-alkyl;each R₂₀, R₂₁, and R₂₂ is selected from H or alkyl; or any two of X₂₀,X₂₁, X₂₂, X₂₃, X₂₄, R₂₀, R₂₁, or R₂₂ can form an optionally substitutedoxygen-containing heterocycle; orpharmaceutically acceptable salts, esters, prodrugs, or metabolitesthereof;or ester derivatives, saccharide derivatives, or —(CH₂CH₂O)_(n)CH₃derivatives thereof, where n is 1 to 100;and a pharmaceutically acceptable excipient.

In a further embodiment, the Het_(o) is an unsubstituted furanyl group.In a further or alternative embodiment, L is a bond.

In a further or alternative embodiment, R₂₁, and R₂₂ are CH₃. In afurther embodiment at least one of

groups is a

. In a further or alternative embodiment, at least one of

groups is a

In a further or alternative embodiment, at least one of

groups is a

In a further or alternative embodiment, X₂₀ is an oxo group. In afurther or alternative embodiment, the compound of Formula II isselected from:

In a further or alternative embodiment, the pharmaceutical compositionhas a therapeutically effective amount of a compound presented in Tables2 or 3, along with pharmaceutically acceptable excipients. In a furtheror alternative embodiment, the pharmaceutical composition has atherapeutically effective amount of a compound isolated from the plantfamilies of order Rutales, including in Maliaceae and Rutaceae. In afurther or alternative embodiment, the pharmaceutical composition has atherapeutically effective amount of a compound derived from a4,4,8-trimethyl-17-furanylsteroid skeleton. In a further or alternativeembodiment, the pharmaceutical composition has a therapeuticallyeffective amount of a compound is a tetranortriterpenoid.

In another aspect provided herein is a method for treating or reducingthe risk of a neurodegenerative condition in a subject in need thereofby administering to the subject a therapeutically effective amount ofany of the above-described neuroprotective compound compositions. Insome embodiments, the sole active ingredient in the pharmaceuticalcomposition administered to the subject is a neuroprotective compounddisclosed herein. In some embodiments, the composition to beadministered to the subject comprises a neuroprotective compound that ata concentration of 10 μM provides at least 6% (e.g., at least 20%, 50%,or 70%) protection against 3 mM 3-nitropropionic acid to rat mixedhippocampal cultures. In some embodiments, the subject is diagnosed assuffering from the neurodegenerative condition prior to administrationof the composition. In some embodiments, administration of thecomposition to the subject is parenteral, intravenous, subcutaneous,intra-muscular, trans-nasal, intra-arterial, transdermal, orrespiratory. In some embodiments, the subject to be treated isadministered, in addition to one of the above-described compositions, acomposition comprising a therapeutically effective amount of apolyphenol (e.g., resveratrol or epigallocatechin 3-gallate) or anantioxidant compound (e.g., Vitamin C or Vitamin E).

In a related aspect, the subject to be treated is suffering from achronic neurodegenerative condition. In some embodiments, the chronicneurodegenerative condition is Alzheimer's disease. In some embodiments,in addition to administering one of the above-described neuroprotectivecompositions to a subject suffering from Alzheimer's Disease, the levelof one or more Alzheimer's Disease prognostic biomarkers is determinedin a biological sample from the subject. In some embodiments, one ormore Alzheimer's Disease prognostic biomarkers to be assayed comprisetau protein, phospho-tau protein, β-amyloid₁₋₄₂ peptide, β-amyloid₁₋₄₀peptide, C1q protein, IL-6 protein, ApoE protein, α-1-antichymotrypsinprotein, oxysterol, isoprostane, 3-nitrotyrosine, or any combinationthereof. In some embodiments, the subject to be treated is sufferingfrom multiple sclerosis. In some embodiments, the subject to be treatedis suffering from Huntington's disease. In some embodiments, the subjectto be treated is suffering from AIDS-related dementia. In someembodiments, the subject to be treated is suffering from schizophrenia.In some embodiments, the subject to be treated is suffering fromAmyotrophic Lateral Sclerosis. In some embodiments, the subject to betreated is suffering from a retinal disease. In some embodiments, thesubject to be treated is suffering from glaucoma, optic neuritis,compressive optic neuropathy, or a hereditary neuropathy. In someembodiments, the subject to be treated is suffering from epilepsy.

In a related aspect, the subject to be treated is suffering from anacute neurodegenerative condition. In some embodiments, the subject tobe treated is suffering from a stroke (e.g., an acute thromboembolicstroke, a focal ischemia, a global ischemia, or a transient ischemicattack). In some embodiments, the subject to be treated is sufferingfrom ischemia resulting from a surgical technique involving prolongedhalt of blood flow to the brain. In some embodiments, the subject to betreated is suffering from head trauma. In some embodiments, the subjectto be treated is suffering from spinal trauma. In some embodiments, thesubject to be treated is suffering from an optic nerve stroke, anteriorischemic optic neuropathy, or traumatic optic neuropathy.

In another aspect provided herein is a method for treating multiplesclerosis in a subject in need thereof by administering to the subject atherapeutically effective amount of any of the above-describedneuroprotective compound compositions.

In a further aspect provided herein is a method for treatingAIDS-related dementia in a subject in need thereof by administering tothe subject a therapeutically effective amount of any of theabove-described neuroprotective compound compositions.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph showing the results of an in vitro screen forneuroprotective compounds performed on a library of compounds (SpectrumCollection from MicroSource Discovery Systems, Inc.) containing FDAapproved compounds, natural products, and other bioactive compounds.

FIG. 2 shows the chemical structures of five of the neuroprotectivecompounds as described herein.

FIG. 3 is a bar graph showing the effect of a series of 3-nitropropionicacid (3-NP) concentrations (0.5-10 mM) on survival of mixed hippocampalcell cultures in a [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) viability assay. Absorbance at 595 nm(corresponding to the absorbance of the reduced MTT formazen product) isdirectly proportional to cell viability.

FIG. 4 is a set of bar graphs showing the results of an MTT viabilityassay of mixed hippocampal cell cultures in which (A) the effect of 3-NP(3 mM) is tested alone or in the presence of neuroprotectiveantioxidants GPI 1046 (1 μM) or Resveratrol (25 μM); and (B) the effectof HIV Tat protein (500 nM) is tested alone or in the GPI 1046 (10 μM)or Resveratrol (10 μM). The statistical significance of data compared toeither 3-NP or Tat treatment (right panel) is indicated by ANOVA, withNewman-Keuls post hoc comparisons. ** indicates p<0.01; *** indicatesp<0.001 (n=8 per treatment). Each experiment was performed intriplicate.

FIG. 5 is a set of bar graphs showing the results of an MTT viabilityassay of mixed hippocampal cell culture in which the effect of 3-NP (3mM) is tested alone or in the presence of (A) Khivorin (10 μM); (B)Isogedunin (10 μM); (C) Angolensic acid, ME; and (D) Odoratone. Thestatistical significance of data compared to 3-NP treatment is indicatedby ANOVA, with Newman-Keuls post hoc comparisons. ** indicates p<0.01;*** p<0.001.

FIG. 6 is a set of bar graphs showing the results of an MTT viabilityassay of mixed hippocampal cell cultures in which the effect of 3-NP (3mM) is tested alone or in the presence of a range of concentrations ofmodified terpenoid compounds (A) Khivorin (0.1-10 μM); (B) Isogedunin(0.1-10 μM); (C) Nomilin (0.5-10 μM); and (D) Limonin (0.1-10 μM).

FIG. 7 is a set of bar graphs showing the results of an MTT viabilityassay of mixed hippocampal cell cultures in which the effect of theneurotoxic HIV Tat protein (500 nM) is tested alone or in the presenceof a series of concentrations of (A) Isogedunin (0.5-10 μM) and (B)Limonin (0.1-10 μM).

FIG. 8 is a set of bar graphs showing the results of an MTT viabilityassay of mixed hippocampal cell cultures in which the effect of (A) NMDA(100 μM) or (B) 6-OHDA (100 μM) is tested alone or in the presence of arange of concentrations of Limonin (0.1-10 μM).

FIG. 9 is a set of bar graphs showing the results of an MTT viabilityassay of human fetal neuron cultures in which the effect of (A) 3-NP (3mM) or (B) 6-OHDA (100 μM) is tested alone or in the presence of a rangeof concentrations of Limonin (0.1-10 μM).

DETAILED DESCRIPTION OF THE INVENTION

The appended claims particularly point out features set forth herein. Abetter understanding of the features and advantages of the presentdisclosure will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples described herein are utilized.

Disclosed herein are neuroprotective compounds that decrease induced orspontaneous neuronal or glial cell death, compositions that include theneuroprotective compounds, and methods of their use in treating aneurodegenerative condition. The neuroprotective compounds describedherein are shown to promote survival of neurons and glia in response tocytotoxic challenges, e.g., oxidative stress. Cytotoxic challenges areassociated with a number of neurodegenerative conditions (see, e.g., Linet al. (2006), Nature, 443(7113):787-795); contact with neurotoxic viralproteins such as HIV Tat (see King et al. (2006), Microbes Infect 2006,8(5):1347-1357); and hypoxia (see Won et al. (2002), J Biochem Mol Biol2002, 35(1):67-86). Accordingly, the neuroprotective compounds,compositions, methods described herein can be used to treat a variety ofneurodegenerative conditions.

In some embodiments, the methods described herein are used to treat achronic neurodegenerative disease, which includes, but is not limitedto, Alzheimer's Disease, Multiple Sclerosis, HIV-associated dementia,Schizophrenia, Huntington's Disease, Parkinson's Disease, AmyotrophicLateral Sclerosis, Multiple System Atrophy, degenerative retinal disease(e.g., macular degeneration), optic neuropathies (e.g., glaucoma, opticnerve stroke, optic neuritis, anterior ischemic optic neuropathy,traumatic optic neuropathy, compressive optic neuropathy, or hereditaryneuropathies, such as Leber's hereditary optic neuropathy),Schizophrenia, Pick's disease, Alexander disease, Alper's disease,Ataxia telangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockaynesyndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease,Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Josephdisease (Spinocerebellar ataxia type 3), Neuroborreliosis,Pelizaeus-Merzbacher Disease, Primary lateral sclerosis, Prion diseases,Refsum's disease, Sandhoff disease, Schilder's disease,Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease),Spinocerebellar ataxia (multiple types with varying characteristics),Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabesdorsalis, or any combination thereof.

In some embodiments, the methods described herein can be used to treatacute neurodegenerative conditions, which include, but are not limitedto stroke (e.g., thromboembolic stroke, focal ischemia, global ischemia,or transient ischemic attack), ischemia resulting from a surgicaltechnique involving prolonged halt of blood flow to the brain, headtrauma, spinal trauma, or any combination thereof.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are described in, e.g., the Diagnostic andStatistical Manual of Mental Disorders, 4^(th) ed., 1994, Am. Psych.Assoc.; and Harrison's Principles of Internal Medicine©,” 16th ed.,2004, The McGraw-Hill Companies, Inc.

For example, where the subject is at risk of or is suffering frommultiple sclerosis, a set of standard criteria, such as the “McDonaldCriteria” can be used for prognosis/diagnosis. See McDonald et al.(2001), Ann Neurol, 50(1):121-127. Magnetic resonance imaging (MRI) ofthe brain and spine can be used to evaluate individuals with suspectedmultiple sclerosis. MRI shows areas of demyelination as bright lesionson T2-weighted images or FLAIR (fluid attenuated inversion recovery)sequences. Gadolinium contrast is used to demonstrate active plaques onT1-weighted images. Further, a prognostic biomarker assay ofcerebrospinal fluid (CSF) obtained by lumbar puncture can provideevidence of chronic inflammation of the central nervous system.Specifically, CSF is tested for oligoclonal bands, which areimmunoglobulins found in 85% to 95% of people with definite MS, albeitnot exclusively in MS patients. Additional criteria for diagnosis ofmultiple sclerosis include, e.g., a reduction in visual evokedpotentials and somatosensory evoked potentials, which are indicative ofdemyelination.

Where a neurodegenerative disorder affects a cognitive ability, asubject can be diagnosed by any one of a number of standardizedcognitive assays, e.g., the Mini-Mental State Examination, the BlessedInformation Memory Concentration assay, or the Functional ActivityQuestionnaire. See, e.g., Adelman et al. (2005), Am. Family Physician,71(9):1745-1750. Indeed, in some cases a subject can also be diagnosedas having a high risk of developing a chronic neurodegenerativecondition (e.g., Alzheimer's disease), even in the absence of overtsymptoms. For example, the risk of Alzheimer's disease in a subject canbe determined by detecting a decrease in the volumes of the subject'shippocampus and amygdala, using magnetic resonance imaging. See, e.g.,den Heijer et al. (2006), Arch Gen Psychiatry, 63(1):57-62. Assay ofprognostic biomarkers in a sample from a subject are also useful inprognosis or diagnosis of a chronic neurodegenerative condition. Forexample, where the chronic neurodegenerative condition is Alzheimer'sdisease, prognostic biomarkers include, but are not limited to, totaltau protein, phospho-tau protein, β-amyloid₁₋₄₂ peptide, β-amyloid₁₋₄₀peptide, complement component 1, q subcomponent (C1q) protein,interleukin 6 (IL-6) protein, apolipoprotein E (APOE) protein,α-1-antichymotrypsin protein, oxysterol (e.g., 24S-hydroxycholesterol),isoprostane (e.g., an F2-isoprostane), 3-nitrotyrosine, homocysteine, orcholesterol, or any combination thereof, e.g., the ratio ofβ-amyloid₁₋₄₂ peptide to β-amyloid₁₋₄₀ peptide.

The type of biological sample utilized in prognostic Alzheimer'sbiomarker assays will vary depending on the prognostic biomarker to bemeasured. Further, the relationship between the level of a prognosticbiomarker and Alzheimer's risk varies depending on the particularbiomarker, as well as on the biological sample in which the level of thebiomarker is determined. In other words, the level of the biomarker in abiological sample may be directly correlated or inversely correlatedwith the risk of Alzheimer's Disease, as summarized in Table 1. TABLE 1ALZHEIMER'S DISEASE PROGNOSTIC BIOMARKERS Biological Correlation toBiomarker Sample Type Dementia Risk Reference tau protein cerebrospinalincreased Hampel et al. (2004), Mol Psychiatry, fluid (CSF) 9: 705-710phospho-tau protein CSF increased Hampel et al. (2004), Arch GenPsychiatry, 61: 95-102 Hansson et al. (2006), Lancet Neurol, 5(3):228-234 β-amyloid₁₋₄₂ peptide CSF decreased Hampel et al. (2004), MolPsychiatry, 9: 705-710 Ratio of β-amyloid₁₋₄₂ plasma decreasedGraff-Radford et al. (2007), Arch Neurol, peptide to β-amyloid₁₋₄₀64(3): 354-362; peptide CSF decreased Hansson et al. (2007), DementGeriatr Cogn Disord, 23(5): 316-20 C1q protein CSF decreased Smyth etal. (1994), Neurobiol Aging, 15(5): 609-614 IL-6 protein plasmaincreased Licastro et al. (2000), J Neuroimmunol, 103: 97-102; CSFincreased Sun et al. (2003), Dement Geriatr Cogn Disord, 16(3): 136-44APOE protein CSF increased Fukuyama et al. (2000), Eur Neurol, 43(3):161-169 α-1-antichymotrypsin plasma increased Dik et al. (2005),Neurology, 64(8): protein 1371-1377. oxysterol CSF increasedPapassotiropoulos et al. (2002), J Psychiatr Res, 36(1): 27-32isoprostane CSF increased Montine et al. (2005), Antioxid Redox Signal,7(1-2): 269-275 3-nitrotyrosine CSF increased Tohgi et al. (1999),Neurosci Lett, 269(1): 52-54 homocysteine plasma increased Seshadri etal. (2002), N Engl J Med, 346(7): 476-83 cholesterol plasma increasedPanza et al. (2006), Neurobiol Aging, 27(7): 933-940

Animal models are useful for establishing a range of therapeuticallyeffective doses of neuroprotective compounds for treating any of theforegoing diseases. For example, animal models of chronicneurodegenerative conditions have been established, e.g., forAlzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis,multiple system atrophy, and Huntington's disease. See, e.g., Spires etal. (2005), NeuroRx., 2(3):447-464; Gold et al. (2006), Brain, 129(8):1953-1971; Wong et al. (2002), Nat. Neurosci., 5(7):633-639, Stefanovaet al. (2005), Am J Pathol, 166(3): 869-876, Tadros et al. (2005),Pharmacol Biochem Behav; 82(3):574-582. These animal models develop achronic neurodegenerative condition that is manifested behaviorally byimpaired learning, memory, or locomotion. Cognitive abilities, as wellas motor functions in non-human animals suffering from a chronicneurodegenerative condition can be assessed using a number of behavioraltasks. Well-established sensitive learning and memory assays include theMorris Water Maze (MWM), context-dependent fear conditioning, cued-fearconditioning, and context-dependent discrimination. See, e.g., Anger(1991), Neurotoxicology, 12(3):403-413. Locomotor behavior, e.g.,following spinal trauma, is commonly assessed using a 21-point openfield locomotion score assay developed by Basso, Beattie, and Bresnahan(BBB) (Basso, et al. (1995), J Neurotrauma, 12(1): 1-21). Such animalmodels are suitable for testing effective dose ranges for theneuroprotective compounds and Compositions described herein as well asfor identifying additional neuroprotective compounds.

Certain Chemical Terminology

All patents, patent applications, published materials referred tothroughout the entire disclosure herein, unless noted otherwise, areincorporated by reference in their entirety. In the event that there area plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include,” “includes,” and “included,” is not limiting. The sectionheadings used herein are for organizational purposes only and are not tobe construed as limiting the subject matter described. All documents, orportions of documents, cited in the application including, but notlimited to, patents, patent applications, articles, books, manuals, andtreatises are hereby expressly incorporated by reference in theirentirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology are employed.Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

An “alkyl” group refers to a straight-chained, branched or cyclicaliphatic hydrocarbon group. The “alkyl” moiety may have 1 to 10 carbonatoms (whenever it appears herein, a numerical range such as “1 to 10”refers to each integer in the given range; e.g., “1 to 10 carbon atoms”means that the alkyl group may have 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group of the compoundsdescribed herein may be designated as “C₁-C₄ alkyl” or similardesignations. By way of example only, “C₁-C₄ alkyl” indicates that thereare one to four carbon atoms in the alkyl chain, i.e., the alkyl chainis selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Thus C₁-C₄ alkyl includes C₁-C₂ alkyland C₁-C₃ alkyl. Alkyl groups can be substituted or unsubstituted.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, 2-hydroxyethyl, 2,3-dihydroxypropyl,and 1-(hydroxymethyl)-2-hydroxyethyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith at least one alkoxy group, as defined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides can be found in Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “carbocyclic” or “carbocycle” refers to a compound whichcontains one or more covalently closed ring structures, and that theatoms forming the backbone of the ring are all carbon atoms. The termthus distinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.Carbocycles include cycloalkyls and aryls.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and may be saturated, partiallyunsaturated, or fully unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms. Illustrative examples of cycloalkylgroups include the following moieties:

and the like. Depending on the structure, an cycloalkyl group can be amonoradical or a diradical (e.g., an cycloalkylene group).

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-cycloalkylalkyl limiting cycloalkylalkylgroups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl,cyclohexylmethyl, and the like.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters can be found in Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another. The terms“fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groupsrespectively, in which the halo is fluorine. In certain embodiments,haloalkyls are optionally substituted.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms are selectedfrom an atom other than carbon, e.g., oxygen, nitrogen, sulfur, silicon,phosphorus or combinations thereof.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three, four, five, six, seven, eight, nine, or morethan nine atoms. Heterocycloalkyl rings can be optionally substituted.In certain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples of heterocycloalkyls include, but arenot limited to, lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

the like. The term heteroalicyclic also includes all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

“Heterocycloalkylalkyl” refers to an alkyl group, as defined herein,substituted with a heterocycloalkyl, as defined herein.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Herein, whenever the number of carbonatoms in a heterocycle is indicated (e.g., C₁-C₆ heterocycle), at leastone other atom (the heteroatom) must be present in the ring.Designations such as “C₁-C₆ heterocycle” refer only to the number ofcarbon atoms in the ring and do not refer to the total number of atomsin the ring. It is understood that the heterocylic ring can haveadditional heteroatoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Inheterocycles that have two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Binding to a heterocycle can be at aheteroatom or via a carbon atom. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one. Depending on thestructure, a heterocycle group can be a monoradical or a diradical(i.e., a heterocyclene group). Phosphorous-containing rings include, butare not limited to, 1-oxo-phospholanyl, 1-methyl-1-oxo-phosphinan-4-yl,1-phenyl-1-oxo-phosphinan-4-yl,1-(cyclopropylmethyl)-1-oxo-phosphinan-4-yl,4-methyl-4-oxo-[1,4]azaphosphinan-1-yl,4-phenyl-4-oxo-[1,4]azaphosphinan-1-yl, and4-(cyclopropylmethyl)-4-oxo-[1,4]azaphosphinan-1-yl.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the term “O-carboxy” or “acyloxy” refers to a group offormula RC(═O)O—.

“Alkylcarbonyloxy” refers to a (alkyl)-C(═O)O— group.

As used herein, the term “alkoxycarbonyl” refers to a group of formula—C(═O)OR.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

“Acyl” refers to the group —C(O)R.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, carbonyl, isocyanato, thiocyanato, isothiocyanato, nitro,perhaloalkyl, fluoroalkyl, silyl, and amino, including mono- anddi-substituted amino groups, and the protected derivatives thereof. Byway of example an optional substituents may be L_(s)R_(s), wherein eachL_(s) is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—,—NHC(O)O—, -(substituted or unsubstituted C₁-C₆ alkyl), or -(substitutedor unsubstituted C₂-C₆ alkenyl); and each R₅ is independently selectedfrom H, (substituted or unsubstituted C₁-C₄alkyl), (substituted orunsubstituted C₃-C₆cycloalkyl), heteroaryl, or heteroalkyl.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers, ifdesired, may be obtained, for example, by the separation ofstereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Neuroprotective Compounds

The neuroprotective compounds for use in the pharmaceutical compositionsand methods described herein are compounds of Formula I, Formula II,and/or compounds found in Tables 2 and 3.

Neuroprotective compounds suitable for the methods described herein alsocan come from a variety of sources including both natural (e.g., plantextracts) and synthetic. For example, neuroprotective compounds fallingwithin the class of triterpenes can be extracted from plants of theorder Rutales, e.g., from extracts of seeds, oils, kernels, leaves andbark of various plants from the Meliaceae family, including Neem andMahogany. See, e.g., Roy et al. (2006), Biol Pharm Bull, 29(2):191-201.

The neuroprotective compounds described herein are identified orcharacterized in an in vitro cellular assay, e.g., an assay thatdetermines the viability of neurons or glia in the presence of acytotoxic challenge and one or more concentrations of a candidateneuroprotective compound. Such assays are useful for identifying andtesting the in vitro neuroprotective potency of candidateneuroprotective compounds.

For example, a cell viability assay can be used in a preliminary screenon a large series of compounds each of which is tested at a fixedconcentration. In some embodiments, mixed hippocampal cell cultures areprepared as described in, e.g., Haughey et al. (1999), J Neurochem,73(4):1363-1374, and Haughey et al (2004), J Neurosci, 24(1):257-268.Subsequently, the cultures are pretreated for one hour in the presenceof a candidate neuroprotective agent and then incubated with a cytotoxicagent for about 18 hours. Examples of cytotoxic agents include, but arenot limited to, oxidative stressors (e.g., 3-nitropropionic acid (3-NP)or H₂O₂), excitatory amino acids (e.g., kainate), or neurotoxic proteins(e.g., Hiv Tat, or Aβ peptides). If the survival of cell cultures in thepresence of the candidate compound and the cytotoxic agent (e.g., 3-NP)is significantly greater than that of cultures incubated with thecytotoxic agent alone, the candidate test compound is considered to haveneuroprotective activity. The level of protection (“percent protection”)provided by the test compound at a given test concentration in vitro canbe expressed as:$\frac{\left\lbrack {\left( {{{Cell}\quad{Viability}\quad{with}\quad{Cytoxic}\quad{agent}} + {{Test}\quad{Compound}}} \right) - \left( {{Cell}\quad{Viability}\quad{with}\quad{Cytoxic}\quad{agent}\quad{alone}} \right)} \right\rbrack}{\left\lbrack \left( {{{Control}\quad{Cell}\quad{Viability}\quad\left( {{medium}\quad{alone}} \right)} - \left( {{Cell}\quad{Viability}\quad{with}\quad{Cytotoxic}\quad{agent}\quad{alone}} \right)} \right\rbrack \right.} \times 100$

In some embodiments, at a concentration of 10 μM, a neuroprotectivecompound described herein, provides at least 6% protection against acytotoxic agent, i.e., at least 7%, 15%, 18%, 19%, 20%, 23%, 26%, 28%,32%, 33%, 36%, 38%, 39%, 42%, 50%, 54%, 56%, 58%, 61%, 65%, 69%, 70%,77%, 82%, 84%, 97%, or any other percent from at least 6% to 100%protection against the cytotoxic agent.

In some embodiments, at a concentration of 10 μM, a neuroprotectivecompound described herein, provides greater than 100% protection, whichsignifies that, in addition to blocking cytotoxic agent-induced celldeath, the neuroprotective compound also inhibits spontanteous celldeath in the control cell cultures (i.e., cultures exposed to mediumalone). In some embodiments, a neuroprotective compound described hereinprovides, e.g., 101, 128%, 129, or 151% protection.

A variety of methods for determining cell viability may be used. In someembodiments, cell viability is assessed based on the “MTT” assay methoddescribed in Mosmann (1983), J Immunol Methods, 65(1-2):55-63, or avariant thereof. This assay is based on the ability of a mitochondrialdehydrogenase enzyme from viable cells to cleave the tetrazolium ringsof the pale yellow MTT and form dark blue formazan crystals, which aretrapped in cells and readily quantified by ELISA spectrophotometry.

High throughput cell viability assays may be used, and are particularlyuseful for screening, with routine effort, a great number of candidateneuroprotective compounds or structural variants of identifiedneuroprotective compounds, e.g., structural variants of Formula I orFormula II described herein. See, e.g., J Biomol Screen, 9(6):506-515;Carrier et al. (2006), J Neurosci Methods, 154(1-2):239-244; See, e.g.,In addition, high throughput screening systems are commerciallyavailable (see, e.g., Zymark Corp., Hopkinton, Mass.; Air TechnicalIndustries, Mentor, Ohio; Beckman Instruments, Inc. Fullerton, Calif.;Precision Systems, Inc., Natick, Mass., etc.). These systems typicallyautomate entire procedures including all sample and reagent pipetting,liquid dispensing, timed incubations, and final readings of themicroplate in detector(s) appropriate for the assay. Automated systemsthereby allow the identification and characterization of a large numberof neuroprotective compounds of Formula I or Formula II without undueeffort.

The neuroprotective compounds described herein, e.g., those of Formula Ior Formula II, can be used for the manufacture of a medicament fortreating any of the foregoing neurodegenerative conditions (e.g.,multiple sclerosis, Alzheimer's disease, stroke, or spinal cord injury).

In some embodiments, a neuroprotective compound used for the methodsdescribed herein in vitro ED₅₀ for neuroprotection of less than 100 μM(e.g., less than 10 μM, less than 5 μM, less than 4 μM, less than 3 μM,less than 1 μM, less than 0.8 μM, less than 0.6 μM, less than 0.5 μM,less than 0.4 μM, less than 0.3 μM, less than less than 0.2 μM, lessthan 0.1 μM, less than 0.08 μM, less than 0.06 μM, less than 0.05 μM,less than 0.04 μM, less than 0.03 μM, less than less than 0.02 μM, lessthan 0.01 μM, less than 0.0099 μM, less than 0.0098 μM, less than 0.0097μM, 0.0096 μM, less than 0.0095 μM, less than 0.0094 μM, less than0.0093 μM, less than 0.00092, or less than 0.0090 μM).

Examples of Pharmaceutical Compositions and Methods of Administration

The pharmaceutical solid dosage forms described herein can include acompound of Formula I or Formula II, and one or more pharmaceuticallyacceptable additives such as a compatible carrier, binder, fillingagent, suspending agent, flavoring agent, sweetening agent,disintegrating agent, dispersing agent, surfactant, lubricant, colorant,diluent, solubilizer, moistening agent, plasticizer, stabilizer,penetration enhancer, wetting agent, anti-foaming agent, antioxidant,preservative, or one or more combination thereof. In still otheraspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula I orFormula II. In one embodiment, some or all of the particles of thecompound of Formula I or Formula II are coated. In another embodiment,some or all of the particles of the compound of Formula I or Formula IIare microencapsulated. In still another embodiment, the particles of thecompound of Formula I or Formula II are not microencapsulated and areuncoated.

Pharmacological techniques include, e.g., one or a combination ofmethods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry ornon-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g.,Lachman et al., “The Theory and Practice of Industrial Pharmacy” (1986).Other methods include, e.g., spray drying, pan coating, meltgranulation, granulation, fluidized bed spray drying or coating (e.g.,wurster coating), tangential coating, top spraying, tableting, extrudingand the like.

Provided herein are pharmaceutical compositions that include one or moreneuroprotective compounds described herein and a pharmaceuticallyacceptable diluent(s), excipient(s), or carrier(s). In addition, thecompounds described herein can be administered as pharmaceuticalcompositions in which compounds described herein are mixed with otheractive ingredients, as in combination therapy. In some embodiments, thepharmaceutical compostions may include other medicinal or pharmaceuticalagents, carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In addition, the pharmaceutical compositionscan also contain other therapeutically valuable substances.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In other embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, compounds of Formula Ior Formula II with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a neurodegenerative condition, disease,or disorder to be treated. Preferably, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity and stage of the of the condition, the age and relative healthof the subject, the potency of the compound used and other factors. Thecompounds can be used singly or in combination with one or moretherapeutic agents as components of mixtures.

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release ions, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured, by way of example only, by means of mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or compression processes.

The pharmaceutical compositions will include at least one compounddescribed herein, such as, for example, a compound of Formula I orFormula II, as an active ingredient in free-acid or free-base form, orin a pharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as, compounds of Formula I or Formula II, that isdelivered into the general circulation of the animal or human beingstudied. The total exposure (AUC(0-∞)) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which compounds disclosedherein, such as, compounds of Formula I or Formula II that are absorbedinto the general circulation when the pharmaceutical composition istaken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as, compounds of Formula I or Formula II, in theplasma component of blood of a subject. It is understood that the plasmaconcentration of compounds of Formula I or Formula II may varysignificantly between subjects, due to variability with respect tometabolism and/or possible interactions with other therapeutic agents.In accordance with one embodiment disclosed herein, the blood plasmaconcentration of the compounds of Formula I or Formula II may vary fromsubject to subject. Likewise, values such as maximum plasmaconcentration (Cmax) or time to reach maximum plasma concentration(Tmax), or total area under the plasma concentration time curve(AUC(0-∞)) may vary from subject to subject. Due to this variability,the amount necessary to constitute “a therapeutically effective amount”of a compound of Formula I or Formula II may vary from subject tosubject.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withcompounds disclosed herein, such as, compounds of Formula I or FormulaII, and the release profile properties of the desired dosage form.Exemplary carrier materials include, e.g., binders, suspending agents,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, wetting agents, diluents, and the like.“Pharmaceutically compatible carrier materials” may include, but are notlimited to, acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents, including, but not limited toa phosphate buffered saline solution. In certain embodiments, diluentsincrease bulk of the composition to facilitate compression or createsufficient bulk for homogenous blend for capsule filling. Such compoundsinclude e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

The term “effective amount,” as used herein, refers to a sufficientamount of an agent or a compound being administered which will relieveto some extent one or more of the symptoms of the disease or conditionbeing treated. The result can be reduction and/or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. An appropriate “effective” amount in anyindividual case may be determined using techniques, such as a doseescalation study.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or l of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

The terms “neuroprotective,” “neuroprotection,” or “neuroprotectant,” asused herein refer to the ability of an agent (e.g., a compound describedherein) to significantly prevent or reduce the occurrence of spontaneousor induced death (e.g., by apoptosis) of neurons or glia in vitro or invivo, relative to the ability of a control reagent (e.g., cell culturemedium, or a drug vehicle such as DMSO).

A “prognostic biomarker,” as referred to herein, is any molecular,biochemical, metabolic, cellular, or structural entity (or a ratio ofsuch entities), the presence or level of which relates to a likelihoodof developing, suffering from, or having a relapse of a pathologicalcondition.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

The term “subject” as used herein, refers to an animal which is theobject of treatment, observation or experiment. By way of example only,a subject may be, but is not limited to, a mammal including, but notlimited to, a human.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

The compositions described herein can be formulated for administrationto a subject via any means including, but not limited to, oral,parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal,intranasal, rectal or transdermal administration routes. As used herein,the term “subject” is used to mean an animal, preferably a mammal,including a human or non-human. The terms patient and subject may beused interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude a compound of Formula I or Formula II, can be formulated intoany suitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions andthe like, for oral ingestion by a patient to be treated, solid oraldosage forms, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the present invention may be administeredas a single capsule or in multiple capsule dosage form. In someembodiments, the pharmaceutical formulation is administered in two, orthree, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula I or Formula II, with one or more pharmaceutical excipients toform a bulk blend composition. When referring to these bulk blendcompositions as homogeneous, it is meant that the particles of thecompound of Formula I or Formula II, are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms, such as tablets, pills, andcapsules. The individual unit dosages may also include film coatings,which disintegrate upon oral ingestion or upon contact with diluent.These formulations can be manufactured by pharmacological techniques.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds of Formula I or Formula II, whichsufficiently isolate the compound of Formula I or Formula II from othernon-compatible excipients. Materials compatible with compounds ofFormula I or Formula II are those that delay the release of thecompounds of Formula I or Formula II in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds of Formula I or Formula II,include, but are not limited to, hydroxypropyl cellulose ethers (HPC)such as Klucel® or Nisso HPC, low-substituted hydroxypropyl celluloseethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such asSeppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS,PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymerssuch as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat(HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mixturesthereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinylalcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such asNatrosol®, carboxymethylcelluloses and salts of carboxymethylcelluloses(CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycolco-polymers such as Kollicoat IR®, monoglycerides (Myverol),triglycerides (KLX), polyethylene glycols, modified food starch, acrylicpolymers and mixtures of acrylic polymers with cellulose ethers such asEudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55,Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100,Eudragit® L12.5, Eudragit® S112.5, Eudragit® NE30D, and Eudragit® NE40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC andstearic acid, cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds of Formula I or Formula II may beformulated. Such methods include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In one embodiment, the particles of compounds of Formula I or Formula IIare microencapsulated prior to being formulated into one of the aboveforms. In still another embodiment, some or most of the particles arecoated prior to being further formulated by using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000). In other embodiments, the solid dosageformulations of the compounds of Formula I or Formula II are plasticized(coated) with one or more layers. Illustratively, a plasticizer isgenerally a high boiling point solid or liquid. Suitable plasticizerscan be added from about 0.01% to about 50% by weight (w/w) of thecoating composition. Plasticizers include, but are not limited to,diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, triacetin, polypropylene glycol, polyethyleneglycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol,stearate, and castor oil.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound of Formula I or Formula II,can be further formulated to provide a controlled release of thecompound of Formula I or Formula II. Controlled release refers to therelease of the compound of Formula Formula I or Formula II from a dosageform in which it is incorporated according to a desired profile over anextended period of time. Controlled release profiles include, forexample, sustained release, prolonged release, pulsatile release, anddelayed release profiles. In contrast to immediate release compositions,controlled release compositions allow delivery of an agent to a subjectover an extended period of time according to a predetermined profile.Such release rates can provide therapeutically effective levels of agentfor an extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the practice of the present invention toachieve delivery to the lower gastrointestinal tract. In someembodiments the polymers for use in the present invention are anioniccarboxylic polymers.

In other embodiments, the formulations described herein, which include acompound of Formula I or Formula II, are delivered using a pulsatiledosage form. A pulsatile dosage form is capable of providing one or moreimmediate release pulses at predetermined time points after a controlledlag time or at specific sites. Pulsatile dosage forms including theformulations described herein, which include a compound of Formula I orFormula II, may be administered using a variety of pulsatileformulations. For example, such formulations include, but are notlimited to, those described in U.S. Pat. Nos. 5,011,692, 5,017,381,5,229,135, and 5,840,329. Other pulsatile release dosage forms suitablefor use with the present formulations include, but are not limited to,for example, U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040,5,567,441 and 5,837,284. In one embodiment, the controlled releasedosage form is pulsatile release solid oral dosage form including atleast two groups of particles, (i.e. multiparticulate) each containingthe formulation described herein. The first group of particles providesa substantially immediate dose of the compound of Formula I or FormulaII upon ingestion by a mammal. The first group of particles can beeither uncoated or include a coating and/or sealant. The second group ofparticles includes coated particles, which includes from about 2% toabout 75%, preferably from about 2.5% to about 70%, and more preferablyfrom about 40% to about 70%, by weight of the total dose of the compoundof Formula I or Formula II in said formulation, in admixture with one ormore binders. The coating includes a pharmaceutically acceptableingredient in an amount sufficient to provide a delay of from about 2hours to about 7 hours following ingestion before release of the seconddose. Suitable coatings include one or more differentially degradablecoatings such as, by way of example only, pH sensitive coatings (entericcoatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit®&L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit®S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5,and Eudragit® NE30D, Eudragit® NE 40D®) either alone or blended withcellulose derivatives, e.g., ethylcellulose, or non-enteric coatingshaving variable thickness to provide differential release of theformulation that includes a compound of Formula I or Formula II.

Additional examples of controlled release delivery systems include,e.g., polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using binders and the like. See, e.g., Liberman etal., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990);Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to the particles of compound of Formula I or Formula II, theliquid dosage forms may include additives, such as: (a) disintegratingagents; (b) dispersing agents; (c) wetting agents; (d) at least onepreservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH 105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions include, for example, hydrophilic polymers,electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP;commercially known as Plasdone®), and the carbohydrate-based dispersingagents such as, for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMCK100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulosesodium, methylcellulose, hydroxyethylcellulose,hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-celluloseacetate stearate, noncrystalline cellulose, magnesium aluminum silicate,triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinylacetate copolymer (Plasdone®, e.g., S-630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88, and F108, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsinclude, but are not limited to, cetyl alcohol, glycerol monostearate,polyoxyethylene sorbitan fatty acid esters (e.g., the commerciallyavailable Tweens® such as e.g., Tween 20® and Tween 80® (ICI SpecialtyChemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®,and Carbopol 934® (Union Carbide)), oleic acid, glyceryl monostearate,sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate,triacetin, vitamin E TPGS, sodium taurocholate, simethicone,phosphotidylcholine and the like

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Inone embodiment, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.001% toabout 1.0% the volume of the aqueous dispersion. In another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.005% to about0.5% the volume of the aqueous dispersion. In yet another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.01% to about1.0% the volume of the aqueous dispersion.

In addition to the additives listed above, the liquid formulations canalso include inert diluents such as water or other solvents,solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol,cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such ascottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, andsesame oil, glycerol, tetrahydrofturfuryl alcohol, polyethylene glycols,fatty acid esters of sorbitan, or mixtures of these substances, and thelike.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein.

Intranasal formulations of a compound of Formula I or Formula II can beprepared by adapting the methods described in U.S. Pat. Nos. 4,476,116,5,116,817 and 6,391,452. Formulations that include a compound of FormulaI or Formula II, which are prepared according to these and othertechniques are prepared as solutions in saline, employing benzyl alcoholor other suitable preservatives, fluorocarbons, and/or othersolubilizing or dispersing agents. See, for example, Ansel, H. C. etal., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed.(1995). Preferably these compositions and formulations are prepared withsuitable nontoxic pharmaceutically acceptable ingredients. Theseingredients can be found in REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY, 21 st edition, 2005, a standard reference in the field. Thechoice of suitable carriers is highly dependent upon the exact nature ofthe nasal dosage form desired, e.g., solutions, suspensions, ointments,or gels. Nasal dosage forms generally contain large amounts of water inaddition to the active ingredient. Minor amounts of other ingredientssuch as pH adjusters, emulsifiers or dispersing agents, preservatives,surfactants, gelling agents, or buffering and other stabilizing andsolubilizing agents may also be present. Preferably, the nasal dosageform should be isotonic with nasal secretions.

For administration by inhalation, the compounds of Formula Formula I orFormula II described herein may be in a form as an aerosol, a mist or apowder. Pharmaceutical compositions described herein are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compounddescribed herein and a suitable powder base such as lactose or starch.

Buccal formulations that include compounds of Formula I or Formula IImay be administered using a variety of formulations. For example, suchformulations include, but are not limited to, U.S. Pat. Nos. 4,229,447,4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosageforms described herein can further include a bioerodible (hydrolysable)polymeric carrier that also serves to adhere the dosage form to thebuccal mucosa. The buccal dosage form is fabricated so as to erodegradually over a predetermined time period, wherein the delivery of thecompound of Formula I or Formula II, is provided essentially throughout.Buccal drug delivery avoids the disadvantages encountered with oral drugadministration, e.g., slow absorption, degradation of the active agentby fluids present in the gastrointestinal tract and/or first-passinactivation in the liver. With regard to the bioerodible (hydrolysable)polymeric carrier, it will be appreciated that virtually any suchcarrier can be used, so long as the desired drug release profile is notcompromised, and the carrier is compatible with the compound of FormulaI or Formula II, and any other components that may be present in thebuccal dosage unit. Generally, the polymeric carrier compriseshydrophilic (water-soluble and water-swellable) polymers that adhere tothe wet surface of the buccal mucosa. Examples of polymeric carriersuseful herein include acrylic acid polymers and co, e.g., those known as“carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is onesuch polymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gels.

Transdermal formulations described herein may be administered using avariety of devices that include, but are not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients. In one embodiments, thetransdermal formulations described herein include at least threecomponents: (1) a formulation of a compound of Formula I or Formula II;(2) a penetration enhancer; and (3) an aqueous adjuvant. In addition,transdermal formulations can include additional components such as, butnot limited to, gelling agents, creams and ointment bases, and the like.In some embodiments, the transdermal formulation can further include awoven or non-woven backing material to enhance absorption and preventthe removal of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein can maintaina saturated or supersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds of Formula I or FormulaII. The rate of absorption can be slowed by using rate-controllingmembranes or by trapping the compound within a polymer matrix or gel.Conversely, absorption enhancers can be used to increase absorption. Anabsorption enhancer or carrier can include absorbable pharmaceuticallyacceptable solvents to assist passage through the skin. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

Formulations that include a compound of Formula I or Formula II,suitable for intramuscular, subcutaneous, or intravenous injection mayinclude physiologically acceptable sterile aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, and sterile powdersfor reconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. For otherparenteral injections, appropriate formulations may include aqueous ornonaqueous solutions, preferably with physiologically compatible buffersor excipients.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingsuppository bases such as cocoa butter or other glycerides, as well assynthetic polymers such as polyvinylpyrrolidone, PEG, and the like. Insuppository forms of the compositions, a low-melting wax such as, butnot limited to, a mixture of fatty acid glycerides, optionally incombination with cocoa butter is first melted.

In other embodiments, the formulations described herein, which include acompound of Formula I or Formula II, are blood brain barrier-permeable(BBB-permeable) nanoparticle formulations. Methods of producing suchBBB-permeable nanoparticle formulations include, but are not limited to,for example, U.S. Pat. Nos. 6,117,454 and 7,025,991.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the treatment of neurodegenerative diseases orconditions that would benefit, at least in part, from neuroprotection.In addition, a method for treating any of the diseases or conditionsdescribed herein in a subject in need of such treatment, involvesadministration of pharmaceutical compositions containing at least onecompound of Formula I or Formula II described herein, or apharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment will typically be in the range of 0.02-5000 mg per day,preferably 1-1500 mg per day. The desired dose may conveniently bepresented in a single dose or as divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.01 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, including, but not limitedto, humans, is in the range from about 0.5 mg to about 100 mg,conveniently administered in divided doses, including, but not limitedto, up to four times a day or in extended release form. Suitable unitdosage forms for oral administration include from about 1 to 50 mgactive ingredient. The foregoing ranges are merely suggestive, as thenumber of variables in regard to an individual treatment regime islarge, and considerable excursions from these recommended values are notuncommon. Such dosages may be altered depending on a number ofvariables, not limited to the activity of the compound used, the diseaseor condition to be treated, the mode of administration, the requirementsof the individual subject, the severity of the disease or conditionbeing treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD50 (the dose lethal to 50% of the population) and the ED50 (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD50 and ED50. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED50 with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The neuroprotective compound compositions described herein can also beused in combination with other therapeutic reagents that are selectedfor their therapeutic value for the condition to be treated. In general,the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes.

In certain instances, it may be appropriate to administer at least oneneuroprotective compound described herein in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the neuroprotectivecompounds described herein is nausea, then it may be appropriate toadminister an anti-nausea agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withone or more (e.g., one, two, or three) other therapeutic agents (whichalso includes a therapeutic regimen) that also have a therapeuticbenefit. In any case, regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient may simplybe additive of the multiple therapeutic agents or the patient mayexperience a synergistic (i.e., a greater than additive) benefit due totheir specific combination.

The compounds may be administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol) orsequentially, depending upon the nature of the disease, disorder, orcondition, the condition of the patient, and the actual choice ofcompounds used.

In any case, the multiple therapeutic agents (one of which is a compoundof Formula I or Formula II described herein) may be administered in anyorder, or even simultaneously. If simultaneously, the multipletherapeutic agents may be provided in a single, unified form, or inmultiple forms (by way of example only, either as a single pill or astwo separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations is alsoenvisioned.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. The length of treatment can vary for eachsubject. For example, the compound or a formulation containing thecompound can be administered for at least 2 weeks, about 1 month toabout 5 years, and from about 1 month to about 3 years.

Exemplary Therapeutic Agents for Use in Combination with aNeuroprotective Compound

Agents for Treating Multiple Sclerosis

Where a subject is suffering from or at risk of suffering from multiplesclerosis, a neuroprotective compound disclosed herein can be usedtogether with one or more of the following exemplary multiple sclerosistherapeutic agents in any combination: Interferon β-1a, Interferon β-1b,glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®), low dosenaltrexone, Natalizumab (Tysabri®), Sativex®, Aimspro (Goats Serum),Trimesta (Oral Estriol), Laquinimod, FTY720 (Fingolimod), MBP8298,NeuroVax™, Tovaxin™, Revimmune, CHR-1103, BHT-3009, BG-12, Cladribine,daclizumab (Zenapax) Rituximab (Rituxan), cyclophosphamide, Campath,Fampridine-SR, MN-166, Temsirolimus, or RPI-78M.

Agents for Treating Dementia (e.g., Alzheimer's Disease or Aids-RelatedDementia)

Where a subject is suffering from or at risk of suffering from dementia,a neuroprotective compound disclosed herein can be used together withone or more agents or methods for treating dementia in any combination.Examples of therapeutic agents/treatments for treating dementia include,but are not limited to any of the following: Flurizan™ (MPC-7869, rflurbiprofen), memantine, galantamine, rivastigmine, donezipil, tacrine,Aβ₁₋₄₂ immunotherapy, resveratrol, (−)-epigallocatechin-3-gallate,statins, vitamin C, or vitamin E.

Agents for Treating Parkinson's Disease

Where a subject is suffering from or at risk of suffering fromParkinson's Disease, a neuroprotective compound disclosed herein can beused together with one or more agents or methods for treatingParkinson's disease in any combination. Examples of therapeuticagents/treatments for treating Parkinson's Disease include, but are notlimited to any of the following: L-dopa, carbidopa, benserazide,tolcapone, entacapone, bromocriptine, pergolide, pramipexole,ropinirole, cabergoline, apomorphine, lisuride, selegiline, orrasagiline.

Agents for Treating Amyotroyhic Lateral Sclerosis

Where a subject is suffering from or at risk of suffering fromAmyotrophic Lateral Sclerosis, a neuroprotective compound disclosedherein can be used together with one or more agents or methods fortreating Amyotrophic Lateral Sclerosis in any combination. Examples oftherapeutic agents/treatments for treating Parkinson's Disease include,but are not limited to any of the following: riluzole, insulin-likegrowth factor 1, or ketogenic diet.

Agents for Treating Huntington's Disease

Where a subject is suffering from or at risk of suffering fromHuntington's Disease, a neuroprotective compound disclosed herein can beused together with one or more agents or methods for treatingHuntington's Disease in any combination. Examples of therapeuticagents/treatments for treating Huntington's Disease include, but are notlimited to any of the following: dopamine receptor blockers, creatine,CoQ10, minocycline, exercise, antioxidants, antidepressants (notably,but not exclusively, selective serotonin reuptake inhibitors SSRIs, suchas sertraline, fluoxetine, and paroxetine), dopamine antagonists, (e.g.,tetrabenazine), or RNAi-mediated silencing of mutant Huntingtinexpression.

Agents for Treating Autoimmune Inflammatory, or Allergic conditions

Where a subject is suffering from or at risk of suffering from anautoimmune, inflammatory disease, or allergic condition that affects thenervous system (see, e.g., Allan et al. (2003), Philos Trans R Soc LondB Biol Sci, 358(1438):1669-1677), a neuroprotective compound disclosedherein can be used together with one or more of the followingtherapeutic agents in any combination: immunosuppressants (e.g.,tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide,azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids(e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone),non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoicacids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs,or sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Agents for Treating Thromboembolic Disorders

Where a subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated witha neuroprotective compound disclosed herein in any combination with oneor more other anti-thromboembolic agents. Examples ofanti-thromboembolic agents include, but are not limited any of thefollowing: thrombolytic agents (e.g., alteplase anistreplase,streptokinase, urokinase, or tissue plasminogen activator), heparin,tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xainhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a,otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747(prasugrel, LY640315), ximelagatran, or BIBR 1048.

Agents for Treating an HIV Infection

Where the subject is suffering from an HIV infection (e.g., sufferingfrom AIDS), any of the neuroprotective compounds disclosed herein can beadministered to the subject prophylactically or therapeutically to treatAIDs-related dementia in combination with one or more anti-HIV compoundsadministered to treat the HIV infection. Examples of anti-HIV compoundsinclude, but are not limited to, AZT (zidovudine, Retrovir), ddI(didanosine, Videx), 3TC (lamivudine, Epivir), d4T (stavudine, Zerit),abacavir (Ziagen), and FTC (emtricitabine, Emtriva), tenofovir (Viread),efavirenz (Sustiva), nevirapine (Viramune), lopinavir/ritonavir(Kaletra), indinavir (Crixivan), ritonavir (Norvir), nelfinavir(Viracept), saquinavir hard gel capsules (Invirase), atazanavir(Reyataz), amprenavir (Agenerase), fosamprenavir (Telzir), tipranavir(Aptivus), or T20 (enfuvirtide, Fuzeon)

Antipsychotic Compounds

Where the subject is suffering from schizophrenia, which has recentlybeen found to be characterized by a progressive neurodegenerativeprocess (see, e.g., Perez-Neri et al. (2006), Neurochem Res,31(10):1279-1294), any of the neuroprotective compounds disclosed hereincan be administered to the subject prophylactically or therapeuticallyin combination with one or more antipsychotic compounds for treatment ofschizophrenia. Examples of antipsychotic compounds include, but are notlimited to, clozapine, risperidone, olanzapine, quetiapine, ziprasidone,aripiprazole, paliperidone, sertindole, zotepine, amisulpride,bifeprunox, melperone, chlorpromazine (largactil, thorazine),fluphenazine, haloperidol, molindone, thiothixene, thioridazine,trifluoperazine, loxapine, perphenazine, prochlorperazine, pimozide,thiothixene, or zuclopenthixol.

Antiepileptic Compounds

Where the subject is suffering from epilepsy, any of the neuroprotectivecompounds disclosed herein can be administered to the subjectprophylactically or therapeutically in combination with one or moreantiepileptic compounds. Examples of antiepileptic compounds include,but are not limited to, carbamazepine, clobazam, clonazepam,ethosuximide, felbamate, fosphenyloin, flurazepam, gabapentin,lamotrigine, levetiracetam, oxcarbazepine, mephenyloin, phenobarbital,phenyloin, pregabalin, primidone, sodium valproate, tiagabine,topiramate, valproate semisodium, valproic acid, vigabatrin, diazepam,or lorazepam.

Neuroprotective Compounds and Compositions

In some embodiments, one or more of the neuroprotective modifiedterpenoid compounds disclosed herein can be used in combination with oneor more neuroprotective compounds or compositions to treat a subjectsuffering from or at risk of neurodegenerative condition. Examples ofneuroprotective compounds include, but are not limited to, any of thefollowing: resveratrol, GPI 1046, epigallocatechin gallate, α-lipoicacid, Omega-3 fatty acids (e.g., docosahexaenoic acid oreicosapentaenoic acid), Vitamin E (tocopherol), carnitine, cytidinediphosphocoline (citicholine), coenzyme Q10, curcumin, salviolonic acidB, folic acid, Gingko biloba extract, ginsenoside Rb1, ginsenoside Rg3,L-Glutathione, grape seed extract, lutein, zeaxanthin, methylcobalamin,N-acetyl-L-cysteine, pycnogenol, quercetin, or taurine.

EXAMPLES

The following specific examples are to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever. Without further elaboration, it is believed that oneskilled in the art can, based on the description herein, utilize thepresent invention to its fullest extent. All publications cited hereinare hereby incorporated by reference in their entirety. Where referenceis made to a URL or other such identifier or address, it is understoodthat such identifiers can change and particular information on theinternet can come and go, but equivalent information can be found bysearching the internet. Reference thereto evidences the availability andpublic dissemination of such information.

Example 1 Identification of Neuroprotective Compounds

We sought to identify neuroprotective compounds using an in vitroneuroprotection assay as described in detail below. We screened aspecific collection/library of compounds that we identified aspotentially active agents. This particular collection contains 2000compounds of which 50% are FDA-approved compounds, 30% are naturalproducts, and 20% are other bioactive compounds. As shown in FIG. 1, thevast majority of the compounds conferred little or no neuroprotection orwere even neurotoxic, with only about 3% exhibiting neuroprotectiveactivity. From this subset of potential compounds (i.e., thoseexhibiting neuroprotective activity), we selected a further limitedgroup of modified terpenoids. A larger series of modified terpenoidcompounds was then screened in the same type of assay as describedbelow. Exemplary neuroprotective modified terpenoids are shown in FIG.2.

Example 2 Pharmaceutical Compositions Example 2a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of any of Formula I, Formula II, Table 2 or Table 3, isdissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. Themixture is incorporated into a dosage unit form suitable foradministration by injection.

Example 2b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of any of Formula I, Formula II, Table 2 or Table 3, is mixedwith 750 mg of starch. The mixture is incorporated into an oral dosageunit for, such as a hard gelatin capsule, which is suitable for oraladministration.

Example 2c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of any of Formula I, Formula II,Table 2 or Table 3, with 420 mg of powdered sugar mixed, with 1.6 mL oflight corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. Themixture is gently blended and poured into a mold to form a lozengesuitable for buccal administration.

Example 2d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of any of Formula I, Formula II, Table 2 or Table 3, ismixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodiumchloride solution. The mixture is incorporated into an inhalationdelivery unit, such as a nebulizer, which is suitable for inhalationadministration.

Example 2e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of any of Formula I, Formula II, Table 2 or Table 3, is mixedwith 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g ofglycerin and 100 mL of purified water. The resulting gel mixture is thenincorporated into rectal delivery units, such as syringes, which aresuitable for rectal administration.

Example 2f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of any of Formula I, Formula II, Table 2 or Table 3, is mixedwith 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mLof isopropyl myristate and 100 mL of purified alcohol USP. The resultinggel mixture is then incorporated into containers, such as tubes, whichare suitable for topical administration.

Example 2g Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of any of Formula I, Formula II, Table 2 or Table 3, is mixedwith 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2micron filter. The resulting isotonic solution is then incorporated intoophthalmic delivery units, such as eye drop containers, which aresuitable for ophthalmic administration. Example 3: Biological Assays andAnalyses

Example 3A Exemplary Modified Terpenoids are Neuroprotective against anOxidative Stressor and a Neurotoxic Protein

We sought to evaluate the protective efficacy of a number of modifiedterpenoid compounds against the against many different neurotoxins,ranging from the chemotoxic 6-0HDA, NMDA, 3-nitropropionic acid (3-NP),and viral proteins such as Tat and gp120. Thus, we established an invitro neuroprotection assay using rat mixed hippocampal cultures, inwhich we evaluated the protective efficacy of neuroprotective compoundsdisclosed herein. The oxidative stressor 3-NP was used to elicittoxicity in the rat hippocampal cultures to mimic the oxidative damage,reactive oxygen species production and ensuing neurodegenerationresulting from HIV infection. Another measure of neurotoxicity whichresults from HIV infection was evaluated by exposure of the hippocampalcultures to HIV-1 Tat (Li et al (2005), Neurotox Res, 8(1-2):119-134).

Rat mixed hippocamal neuronal cultures were generated from freshlydissected rat hippocampi (embryonic day 18) in neurobasal mediacontaining 5% fetal bovine serum and 2% B27 supplement. The cells wereplated into 96 well plates at a density of 4×10⁵ cells/mL and routinelyused on days 11-14 following culturing. Cell viability was assessed withMTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay. The MTT assay is based on the ability of a mitochondrialdehydrogenase enzyme from viable cells to cleave the tetrazolium ringsof the pale yellow MTT and form dark blue formazan crystals. See Mosmann(1983), J Immunol Methods, 65(1-2):55-63. These crystals are largelyimpermeable to cell membranes, and thus accumulate within healthy cells.The resultant formazan precipitates are solubilized with DMSO and readon a multiwell scanning spectrophotometer (ELISA reader). The number ofsurviving cells is directly proportional to the level of the formazanproduct created.

Mixed hippocampal cultures were incubated with 3-NP (0.5-10 mM) for 18hours and then assessed for viability using an MTT assay. As shown inFIG. 3, titration of 3-NP levels for neurotoxic effects demonstratedthat 3 mM 3-NP treatment consistently induced 25-35% cytotoxicity in ratmixed hippocampal cultures.

The assay system was validated using two neuroprotective agents, GPI1046 and Resveratrol. Both of these compounds has demonstratedantioxidant and/or neuroprotective activities in numerous in vitro andin vivo assays (for review, see Poulter et al. (2004), Neuroscience,128(1):1-6; Caporello, et al. (2006), J Neurochem, 98(1):146-155; Zaminet al. (2006), Neurobiol Dis, 24(1):176-182). Cultures were preincubatedwith GPI 1046 or Resveratrol for one hour prior to an 18 hour exposureto 3 mM 3-NP. These “positive control” neuroprotective compoundssignificantly protected rat neurons from oxidative damage elicited by3-NP (FIG. 4A) in the rat mixed hippocampal culture assay systemdescribed above. The same neuroprotective compounds were evaluated forefficacy against HIV-1 Tat protein toxicity using the same 1 hourpreincubation protocol. As with the 3-NP neurotoxicity assay, thesecompounds protected hippocampal neurons from Tat toxicity as well (FIG.4B). These data indicated that the measurement of neuroprotectionagainst 3-NP toxicity likely serves as a good indicator of protectiveactivity against HIV-1 Tat toxicity.

Using the validated 3 mM 3-NP neurotoxicity assay described above, weevaluated the neuroprotective efficacy of approximately 2000 compoundsfrom the Spectrum Collection (MicroSource Discovery) as described inExample 1. Several of the neuroprotective compounds identified in thiscollection were modified terpenoids. Thus, we tested an expandedcollection of modified terpenoids in the in vitro neuroprotection assay.As shown in Tables 2 and 3, a number of modified terpenoid compoundswere identified as having neuroprotective activity against 3-NP. NPassay data for four of these compounds are shown in FIG. 5. Thesecompounds protected the mixed hippocampal cultures significantly, withnearly complete protection provided by 10 μM of Khivorin, about 60-70%protection resulting from odoratone, and about 50% protection fromgedunin and angolensic acid, methyl ester treatment. The 3-NP protectiondose-response characteristics of the modified terpenoids Khivorin,Gedunin, Nomilin, and Limonin are shown in FIGS. 6A-6D, respectively.Gedunin and Limonin also dose dependently protected hippocampal culturesfrom HIV-1 Tat toxicity (FIG. 7), with nearly complete neuroprotectionprovided by 1-10 μM Gedunin. Thus, some modified terpenoids also protecthippocampal neurons from HIV-1 neurotoxic protein degeneration.

We also tested the ability of Limonin to protect againstN-methyl-D-Aspartic Acid (NMDA) excitotoxicity, and 6-Hydroxydopamine(6-0HDA), a dopaminergic neurotoxin. As shown in FIG. 8, Limonindose-dependently blocked the neurotoxicity of both NMDA (FIG. 8A) and6-OHDA (FIG. 8B) conferring complete protection at the highest Limonindose tested (10 μM).

Finally, we sought to determine if the compounds tested in rat neuronalcultures would also be effective on cultured human fetal neurons.Indeed, as shown in FIG. 9, Limonin dose-dependently protected humanfetal neuronal cultures against both 3-NP (FIG. 9A) and 6-OHDA.

Based on these data, we concluded that various modified terpenoidcompounds are neuroprotective. TABLE 2 Modified Terpenoids havingSignificant 3-NP Neuroprotective Activity Compound Structure %Protection 3alpha- ACETOXYDIHYDRODEOXY- GEDUNIN

151 1,3-DIDEACETYLKHIVORIN

129 DEOXODIHYDROGEDUNIN

101 3beta- ACETOXYDEOXYANGOLENSIC ACID, METHYL ESTER

128 TRIDESACETOXYKHIVORIN

97 7beta-HYDROXY-7- DESACETOXYKHIVORINIC ACID, METHYL ESTER

84 3beta- HYDROXYDEOXODIHYDRO- GEDUNIN

82 DEOXODEOXYDIHYDROGED- UNIN

77 KHIVORIN

70 EPOXYGEDUNIN

69 7-EPIKHIVORIN

65 3beta,7beta- DIACETOXYDEOXODEACE- TOXYDEOXYDIHYDROGEDUNIN

61 DESACETYL (7)KHIVORINIC ACID, METHYL ESTER

58 3-DEOXO-3beta- ACETOXYDEOXYDIHYDRO- GEDUNIN

56 3beta- HYDROXYDEOXODIHYDRO- DEOXYGEDUNIN

56 DEOXYGEDUNOL ACETATE

54 ISOGEDUNIN

50 GEDUNOL

45 2,3-DIHYDROLSOGEDUNIN

44 7-DEACETOXY-7-OXO- KHIVORINIC ACID, METHYL ESTER

42 TRIDESACETOXYKHIVORIN

39 3beta- ACETOXYDEOXODIHYDRO- GEDUNIN

39 DEACETOXY-7-OXOGEDUNIN

38 DEOXYKHIVORIN

36 7-DEACETOXY-7- OXOKHIVORIN

36 3alpha-HYDROXY-3- DEOXYANGOLENSIC ACID METHYL ESTER

35 ANGOLENSIC ACID, METHYL ESTER

33 7-DEAGETYLKHIVORIN

32 3beta- HYDROXYDEOXYDESACE- TOXY-7-OXOGEDUNIN

30 3-alpha- HYDROXYDEOXYGEDININ

28 DIHYDROGEDUNIN

28 6-HYDROXYANGOLENSIC ACID METHYL ESTER

26 1,2alpha- EPOXYDEACETOXYDIHYDRO- GEDUNIN

25 7-DEACETOXY-7- OXODEOXYGEDUNIN

24 DEOXYGEDUNIN

23 GEDUNIN

40 DEACETYLGEDUNIN

19 DIHYDROGEDUNIN ETHANEDITHIOKETAL

19 1,7-DIDEACETOXY-1,7- DIOXO-3- DEACETYLKHIVORIN

15 1,3-DIDEACETYL-7- DEACETOXY-7- OXOKHIVORIN

15 1 (2)alpha- EPOXYDEOXYDIHYDROG- EDUNIN

14

TABLE 3 Modified Terpenoids Exhibiting Neuroprotective Activity against3-NP % Protection Structure vs 3-NP 3beta-ACETOXYDEOXODIHYDROGEDUNIN 39CARAPIN-8(9)-ENE 38 DEACETOXY-7-OXOGEDUNIN 38 KHAYANTHONE 36DEOXYKHIVORIN 36 7-DEACETOXY-7-OXOKHIVORIN 36 ANGOLENSIC ACID, METHYLESTER 33 7-DEACETYLKHIVORIN 32 FISSINOLIDE 28 6-HYDROXYANGOLENSIC ACIDMETHYL ESTER 26 DEOXYGEDUNIN 23 DEACETYLGEDUNIN 19 BUSSEIN 18 CARAPIN 18ENTANDROPHRAGMIN 18 UTILIN 16 1,3-DIDEACETYL-7-DEACETOXY-7- 15OXOKHIVORIN 1,7-DIDEACETOXY-1,7-DIOXO-3- 15 DEACETYLKHIVORIN KHAYASIN C13 DIHYDROFISSINOLIDE 12 8beta-HYDROXYCARAPIN, 3,8-HEMIACETAL 9MEXICANOLIDE 9 QUASSIN 8 3-DEACETYLKHIVORIN 7 PRIEURIANIN 6

Example 3B In Vitro Modeling of Blood Brain Barrier Permeability to TestCompounds

In vitro models of the Blood Brain Barrier from human brainmicrovascular endothelial cells (HBMEC) that were isolated andcharacterized have been published previously (see, e.g., Stins et al.(1997), J Neuroimmunol, 76(1-2):81-90; Cucullo et al. (2007), Epilepsia,48(3):505-516). These HBMEC possess gamma glutamyl transpeptidase (GGTP)and drug transporter P-glycoprotein, and junctional proteins as seen byZO1 immuno-staining, thereby demonstrating their brain endothelial cellcharacteristics. In vitro BBB models were constructed by growing HBMECon microporous membranes (0.4 μm pore size) in the upper compartment ofsemipermeable Transwell™ tissue culture inserts (24 wells,Corning-Costar). The upper compartment compares to blood side and bottomcompartment to brain side. Transmission electron microscopy revealed asmooth endothelial cell monolayer, typical rod shaped Weibel-Paladebodies and tight junctions. Polarity was shown after treatment withTNF-α, which resulted in an apical expression of ICAM-1, which is inagreement with data of Wong et al. (1992), J Neuroimmunol, 39(1-2):11-21. The presence of junctional proteins is seen by ZO1immuno-staining and Western blotting for ZO-1, beta-catenin andoccludin-1, showing that HBMEC possess endothelial and braincharacteristics and functions.

Propidium iodide (PI) (MW=600) at 0.5 mg/ml, an indicator of in vitroblood brain barrier (“BBB”) integrity, is applied to the uppercompartment along with a vehicle solution or a solution containing testcompound at a concentration of 1 μM. At 2 and 4 hours post drugtreatment, levels of compound are measured in top and bottomcompartments by mass spectrometery as described in Tian et al. (2004),Rapid Comm Mass Spec, 18:3099-3104. The level of test compound detectedin the bottom compartment is then normalized for differences in PIpermeability between the test compound solution and the vehicle controlsolution.

Example 3C In Vivo Assessment of Neuroprotective Modified TerpenoidCompounds in a 3-NP-Induced Neurotoxicity Animal Model

In order to determine the in vivo efficacy of compounds identified asneuroprotective against 3-NP in vitro, as described herein, we employ a3-NP-induced neurotoxicity model in rats. See, e.g., Kumar et al.(2006), Behav Pharmacol, 17(5-6):485-492.

To induce 3-NP neurotoxicity in vivo, 12-week-old male Lewis ratsweighing 340-370 gm are administered intraperitoneal injections of 3-NP(20 mg/kg) for 4 days. The animals are divided into three treatmentgroups (n=12 per group) as follows:

Group 1 is administered Khivorin, Gedunin, Odoratone, Angolensic acid,or another modified terpenoid compound once daily (10 mg/kg; oralgavage) beginning four days prior to and continuing for four dayssubsequent to the beginning of the 3-NP injections.

Group 2 is administered saline vehicle (negative control), by oralgavage, beginning four days prior to and continuing for four dayssubsequent to the beginning of the 3-NP injections.

Group 3 is administered resveratrol (positive control) (10 mg/kg; oralgavage) by oral gavage, beginning four days prior to and continuing forfour days subsequent to the beginning of the 3-NP injections.

Subsequent to the beginning of the 3-NP injections, animals are assessedfor significant loss of body weight, a decline in motor function(locomotor activity, movement pattern, and vacuous chewing movements)and cognitive deficits (e.g., impairment in learning or memory).Differences of performance between groups are analyzed at each timepoint by two-tailed t test.

Twenty-four hours after the last 3-NP injection animals areanesthetized, perfused transcardially with saline, followed by ice-cold4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4. Brains areimmediately removed and postfixed overnight in the same fixative andthen cryoprotected in 30% sucrose in 0.1 M phosphate buffer, pH 7.4.Sequential coronal sections (30 μm) are made on a freezing microtome,starting from the anterior aspect of the corpus callosum throughout theentire striatum. For histological assessment, every sixth section (210μm interval) is processed for cresyl violet staining to assess cell lossand neuronal degeneration. Cresyl violet staining is performed withstandard protocols.

Stereological analysis of lesion volumes are performed by digitallyacquiring cresyl violet-stained sections through the striatum at 4×objective using a computerized image analysis system. Lesion volumes foreach group of animals are calculated by summing the cross-sectionalareas of the lesion in each section and multiplying this value by thedistance between sections.

Compounds found to confer a significant reduction in 3-NP-inducedbehavioral deficits or neuroanatomical lesion volume are considered tobe neuroprotective in vivo.

Example 3D In Vivo Assessment of Identified Neuroprotective Compounds ina Focal Ischemia Animal Model

A problem with ongoing methodology used to test the efficacy ofneuroprotective compounds in vivo in the classic Experimental AutoimmuneEncephalomyelitis (EAE) model is that inflammation-mediated lesions arerandomly distributed within the central nervous system, thereby makinguniform quantification of axonal damage and neuronal cell deathdifficult. In contrast, a focal lesion model induces a localizedinflammatory response and subsequent lesion only within a specificregion of the spinal cord. The focal lesion model therefore enables amore accurate assessment of the efficacy of neuroprotective agentsbecause a specific region of the spinal cord and brain are comparedbetween animals. Furthermore, the focal lesion model decreasesvariability found within the classic EAE models and therefore decreasesthe number of animals required.

Lewis rats (12-15 rats per treatment group) are treated with a testcompound at a dose of 0.1, 1, and 10 mg/kg s.c or p.o. or with vehicleonce daily for 3 days prior to immunization with MOG and incompleteFreunds Adjuvant as described below. Eighteen days later, the animalsare subjected to laminectomy of the dorsal column at T8 and injectedwith TNF-α and γ-IFN to induce a focal EAE lesion as described below.Three weeks later, the animals are sacrificed. Outcome measures includebehavioral studies (Basso-Beattie-Bresnahan scale), evoked potentials(nerve conduction velocity), radiological outcomes (Diffusion TensorImaging, Magnetic Resonance Imaging), and histology measurements (LuxolFast Blue, Toluidine Blue, Myelin Basic Protein, phosphoNeurofilamentand Axonal degeneration). A second cohort includes another set ofanimals where the same drug regimen listed above is initiated followingthe laminectomy.

Animals

For these experiments, Lewis rats (10-12 weeks old) are allowed freeaccess to food and water to acclimate 7-10 days before the initiation ofexperiments. At the time of the study, the animals weigh 200-250 g.

Induction of Myelin Oligodendrocyte Glycoprotein (MOG) Sensitivity

Animals are injected subcutaneously at the base of the tail with 100 μlof recombinant MOG₁₋₁₂₅ (250-500 μg/mL) emulsified in incompleteFreund's adjuvant. No manipulations are performed for 18-30 days afterimmunization to allow for the immune system to develop a sensitivity toMOG. This procedure does not induce clinical symptoms of EAE.

Induction of Focal EAE Lesion

To induce an EAE lesion within a specific region of the spinal cord, asteriotaxic injection of TNF-α and IFN-γ is administered within thespinal cord after laminectomy. The animals are shaved prior toinitiation of the procedure. Anesthetized animals are placed in theprone position, and a midline incision is made. Following the dissectionof fascia and muscle, a laminectomy is performed at T8 with Rongeurforceps. A focal EAE lesion within the cortical spinal tract is inducedby administering 2 μL of 250 ng of TNF-α and 150 Units of IFN-γdissolved in phosphate buffered saline with trace amounts of MonastralBlue using a capillary glass tube. Following surgery the wound issutured first through the fascia, and then the skin with a 4.0 vicrylthread or with wound clips. Animals are warmed and allowed to recover.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A pharmaceutical composition, comprising at least one compound havingthe structure of Formula I:

wherein each compound of Formula I is in a substantially purified form;and Y₁ is O and Y₂ is OH or O-alkyl; or Y₁ and Y₂ together form a furangroup; R₁ and R₂ together form a substituted cycloalkyl or cycloalkenylgroup; and

is selected from

, or

wherein X₄ and R₂ together form a substituted heteroalicyclic groupprovided that R₁ is H; or pharmaceutically acceptable salts, prodrugs,or metabolites thereof; or ester derivatives, saccharide derivatives, or—(CH₂CH₂O)_(n)CH₃ derivatives thereof, where n is 1 to 100; and apharmaceutically acceptable excipient.
 2. The pharmaceutical compositionof claim 1, wherein the at least one compound of Formula I has astructure selected from:


3. The pharmaceutical composition of claim 2, wherein the at least onecompound of Formula I has the structure:

wherein R₄ and R₅ together form a substituted cycloalkyl or cycloalkenylgroup.
 4. The pharmaceutical composition of claim 3, wherein the atleast one compound of Formula I has the structure:

wherein R₆ and R₇ together form a substituted cycloalkyl or cycloalkenylgroup; and X₁ is selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl. 5.The pharmaceutical composition of claim 4, wherein the at least onecompound of Formula I has a structure selected from:

wherein R₈ and R₉ are independently H or alkyl; X₂ and X₃ areindependently selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl; and

is selected from

or


6. The pharmaceutical composition of claim 2, wherein the at least onecompound of Formula I has the structure:

wherein R₄ and R₅ together form a substituted cycloalkyl or cycloalkenylgroup.
 7. The pharmaceutical composition of claim 6, wherein the atleast one compound of Formula I has the structure:

wherein R₆ and R₇ together form a substituted cycloalkyl or cycloalkenylgroup; and X₁ is selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl. 8.The pharmaceutical composition of claim 7, wherein the at least onecompound of Formula I has a structure selected from:

wherein R₈ and R₉ are independently H or alkyl; X₂ and X₃ areindependently selected from H, oxo, OH, O-alkyl, or O—C(O)-alkyl; and

is selected from

or


9. The pharmaceutical composition of claim 2, wherein the at least onecompound of Formula I has the structure:

X₄ and R₁₀ together form a substituted heteroalicyclic group.
 10. Thepharmaceutical composition of claim 2, wherein the at least one compoundof Formula I has the structure:

wherein R₁₁ and R₁₂ together form a substituted cycloalkyl orcycloalkenyl group.
 11. The pharmaceutical composition of claim 2,wherein the at least one compound of Formula I has the structure:

wherein R₁₃ and R₁₄ are independently H or alkyl; X₅ is selected from H,oxo, OH, O-alkyl, or O—C(O)-alkyl; and R₁₅ is alkyl-C(O)O-alkyl.
 12. Amethod for treating or reducing the risk of a neurodegenerativecondition in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the pharmaceuticalcomposition of claim
 1. 13. The method of claim 12, wherein, at aconcentration of 10 μM, the compound provides at least about 20%protection against 3 mM 3-nitropropionic acid to rat mixed hippocampalcultures.
 14. The method of claim 12, wherein the subject in needthereof is diagnosed as suffering from the neurodegenerative conditionprior to the administration.
 15. The method of claim 12, wherein theadministration is parenteral, intravenous, subcutaneous, intra-muscular,trans-nasal, intra-arterial, transdermal, or respiratory.
 16. The methodof claim 12, wherein the neurodegenerative condition is a chronicneurodegenerative condition.
 17. The method of claim 16, wherein thechronic neurodegenerative condition is selected from Alzheimer'sDisease, multiple sclerosis, Huntington's Disease, or Parkinson'sDisease.
 18. The method of claim 16, wherein the chronicneurodegenerative condition is AIDS related dementia.
 19. The method ofclaim 16, wherein the chronic neurodegenerative condition is AmyotrophicLateral Sclerosis.
 20. The method of claim 16, wherein the chronicneurodegenerative condition is a retinal disease.
 21. The method ofclaim 16, wherein the chronic neurodegenerative condition is epilepsy.22. The method of claim 12, wherein the neurodegenerative condition isan acute neurodegenerative condition.
 23. The method of claim 22,wherein the acute neurodegenerative condition is stroke.
 24. The methodof claim 23, wherein the stroke is selected from an acute thromboembolicstroke, a focal ischemia, a global ischemia, or a transient ischemicattack.
 25. The method of claim 22, wherein the acute neurodegenerativecondition is an ischemia resulting from a surgical technique involvingprolonged halt of blood flow to the brain.
 26. The method of claim 22,wherein the acute neurodegenerative condition is selected from headtrauma, spinal trauma, optic nerve stroke, anterior ischemic opticneuropathy, or traumatic optic neuropathy.
 27. The method of claim 16,wherein the chronic neurodegenerative condition is glaucoma, opticneuritis, compressive optic neuropathy, or a hereditary neuropathy. 28.The method of claim 16, wherein the chronic neurodegenerative conditionis schizophrenia.
 29. A method for treating multiple sclerosis in asubject in need thereof, comprising administering to the subject acomposition comprising a therapeutically effective amount of thecompound of claim
 1. 30. A method for treating AIDS-related dementia ina subject in need thereof, comprising administering to the subject acomposition comprising a therapeutically effective amount of thecompound of claim 1.